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Title: Clinical reference of tumour infiltrating lymphocytes in colorectal cancer
Keywords: tumour infiltrating lymphocytes, colorectal cancer, 5-FU, predictive significance, single nucleotide polymorphism
Issue Date: 4-Nov-2011
Citation: CHONG PEI YI (2011-11-04). Clinical reference of tumour infiltrating lymphocytes in colorectal cancer. ScholarBank@NUS Repository.
Abstract: Approximately 10-30% of colorectal cancers are characterized with distinctly high densities of tumour-infiltrating lymphocytes (TILS), including CD3+, cytotoxic CD8+, activated cytotoxic CD8+/Granzyme B (GZMB)+, and regulatory T (Treg) FOXP3+ cells. High densities of TILS in CRC have been associated with good prognosis. However, it has been unclear whether the longer survival associated with TILS is due solely to the anti-tumour immune response, or whether this phenotype also responds better to adjuvant treatment. Furthermore, the propensity for certain CRC patients to have high TILS is not well-understood. This thesis aimed to: (i) evaluate the prognostic and predictive significance of TILS and its subtypes. (ii) assess the correlation between the densities of T cell subtypes in the peripheral blood and primary tumours in CRC patients; (iii) characterize the correlations between single nucleotide polymorphisms (SNPs) in CD8a, GZMB and FOXP3 genes in CRC patients and respective gene expression and T cell densities in peripheral blood and tumours. Tissue microarrays containing tumour samples from 439 CRC cases were immunohistochemically evaluated for the densities of CD3, CD8, Granzyme B (GZMB) and FOXP3-positive tumour-infiltrating lymphocytes. The prognostic significance of high CD3+, CD8+, CD8+GZMB+ and FOXP3+ cell density was evaluated in patients treated with surgery alone, while their predictive significance was estimated by comparing the survival of stage III patients treated with or without 5-Fluorouracil (5-FU)-based chemotherapy. Matched peripheral blood samples and tissue sections from 50 CRC patients were analyzed for their T cell densities by flow cytometry and immunohistochemistry respectively. SNPs in CD8a (n=12), GZMB (n=22) and FOXP3 (n=41) were genotyped by Sequenom MassARRAY iPLEX analysis, and examined for their correlation with respectively blood and tumour T cell densities and gene expression levels. High densities of CD3+, CD8+, CD8+GZMB+ and FOXP3+ cells were associated with better overall survival (hazard ratios (HRs) of 0.57-0.67) in univariate (each P<0.05) analysis. Stage III patients with high CD3+, CD8+ and CD8+GZMB+ cell densities and treated with chemotherapy had a better survival than patients treated by surgery alone (HR= 0.18, 0.26 and 0.26, respectively; each P<0.01). Patients with low densities also had a better survival from treatment, but to a lesser degree (HR= 0.55, 0.51 and 0.51, respectively; P=0.11, 0.05 and 0.06, respectively). The degree of inferiority was significant for CD3+ (P=0.032). Densities of each of the T cell subtypes in peripheral blood correlated with respective intra-tumour densities (all P<0.05). Eleven SNPs in blood and 3 in tumour samples were associated with respective T cell densities (P<0.05). The GZMB rs8192922 SNP was the only one associated with both blood and tumour densities, with higher densities of CD8+GZMB+ cells associated with the GG genotype. As conclusions, the improved prognosis of CRC patients with TILS may in part be due to a beneficial interaction between TILS and chemotherapy. CRC patients with TILS may have heightened circulating T cell densities compared to those without TILS. The GZMB rs8192922 GG genotype may be a related factor in these heighted densities. Taken together, the results suggest less invasive genetic and/or peripheral blood monitoring of TILS, and consequent prognostication and prediction of 5-FU response in CRC patients, could be feasible. Future work to validate these findings is required.
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